WCLC 2019 – Tissue tumour mutational burden does not predict response to chemoimmunotherapy in advanced nonsquamous NSCLC


  • Elena Riboldi — Agenzia Zoe
  • Univadis
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Takeaway

  • In KEYNOTE-021 and KEYNOTE-189 trials, tissue tumour mutational burden (tTMB) was not associated with efficacy of carboplatin-pemetrexed alone or in combination with pembrolizumab in patients with untreated metastatic nonsquamous non-small cell lung cancer (NSCLC).

 

Why this matters

  • Limited data on the value of TMB as a biomarker of efficacy are available.

 

Study design

KEYNOTE-021

  • The evaluable population consisted in 12/24 patients of cohorts C (carboplatin-pemetrexed plus pembrolizumab) and 58/123 patients of cohort G (carboplatin-pemetrexed alone [n=26] or carboplatin-pemetrexed plus pembrolizumab [n=32]).

KEYNOTE-189

  • The evaluable population consisted in 293/616 patients treated with pembrolizumab plus chemotherapy (n=207) or placebo plus chemotherapy (n=86).
  • In both studies tTMB was assessed by whole-exome sequencing of tumour tissue and matched normal DNA; tTMB was defined high in case of 175 or more mutations per exome.
  • Association of tTMB with objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) was evaluated.

 

Key results

KEYNOTE-021

  • tTMB as a continuous variable was not significantly associated with ORR, PFS, or OS for pembrolizumab plus chemotherapy (one-sided P=0.180, 0.187, and 0.081, respectively) or chemotherapy alone (one-sided P=0.861, 0.795, and 0.763, respectively).
  • There was no significant correlation between tTMB and PD-L1 expression.
  • In patients treated with pembrolizumab plus chemotherapy, ORR was high irrespective of tTMB status.

KEYNOTE 189

  • tTMB as a continuous variable was not significantly associated with ORR, PFS, or OS for pembrolizumab plus chemotherapy (one-sided P=0.072, 0.075, and 0.174, respectively) or placebo plus chemotherapy (two-sided P=0.434, 0.055, and 0.856, respectively).
  • There was no significant correlation between tTMB and PD-L1 expression.
  • Pembrolizumab plus chemotherapy improved OS, PFS and ORR irrespective of tTMB status.

 

Funding

  • MSD

 

Expert commentary

  • “Identical results in both trials substantiate the first abstract whose numbers were relatively small. Results reinforce previous observation that TMB and PD-L1 independently identify patients who will benefit from treatment with immunotherapy. I wonder if the results would have been the same if the same analysis would have been done on blood.” Melissa L. Johnson, MD, Sarah Cannon Research Institute (Nashville, USA).